This 5-year, two-site A2 competitive renewal of Familial Pathways to Early-Onset Suicide Attempts seeks to identify familial and individual precursors of early-onset suicidal behavior and mechanisms by which suicidal risk is transmitted from parent to child. The cohort consists of 308 offspring of 135 probands with major depressive disorder (MDD) and a history of suicide attempt and a comparison group of 232 offspring of 120 non-attempters probands with MDD, all of whom have been followed for an average of 3.8 years. The aims of the study are to: (1) continue annual follow-up of offspring of attempters and non-attempters in order to document incident and recurrent suicide attempts; (2) characterize all subjects, probands and offspring, on four putative intermediate phenotypes (IP) (impulsive aggressive traits, early-onset depression, neuropsychological function, cortisol response to stress) as well as other risk (e.g., child abuse and neglect) and protective factors (e.g., family cohesion) for suicidal behavior; and (3) examine the role of IPs in mediating the familial transmission of suicidal behavior and predicting new-onset suicide attempts both alone and in interaction with early childhood abuse and neglect. In a projected 4,693 person years of follow-up, a total of 67 new-onset suicide attempts are expected, which will allow for adequate statistical power to test our hypotheses that IPs are familially transmitted, and mediate the familial transmission of suicidal behavior. The identification of IPs will facilitate future genetic studies of suicidal behavior. This study sample is unique because it permits identification of risk factors for familial transmission of suicidal behavior, and the identification of precursors of early-onset suicidal behavior. Because there are now no empirically validated interventions for suicidal youth, the findings from this unique cohort should help to frame treatment targets in high-risk families and individuals designed to alter prodromal at-risk behavior and psychopathology and prevent future suicidal behavior. This study is of public health importance because suicidal behavior is the single biggest risk factor for completed suicide, which is the third leading cause of death among adolescents and young adults in the United States. The aims of this study are consistent with several priorities of the NIMH and the Division of Pediatric Translational Research (DPTR): (1) reduction of the public health burden of suicide and suicidal behavior; (2) inclusion of family-genetic approaches to elucidate the interplay of biological and environmental factors to childhood psychopathology and to identify behavioral and biological markers of vulnerability and resilience; and (3) research that is likely to lead to novel psychosocial and pharmacological preventive and therapeutic interventions. This application is from the New York site (PI: J. John Mann, MH056390). PUBLIC HEALTH RELEVANCE: This study, Familial Pathways to Early-Onset Suicidal Behavior, seeks to identify the familial and individual precursors of early-onset suicidal behavior and the mechanisms by which suicidal risk is transmitted from parent to child. We anticipate that certain traits, namely impulsive aggressive traits, early-onset depression, memory and decision making ability, and a greater physiological reaction to stress (measured by cortisol secretion) are familial and will: (1) explain how suicidal behavior runs in families; (2) predict suicidal behavior in the children of parents who have attempted suicide; and (3) yield intermediate phenotypes that can advance genetic studies of suicidal behavior. This study is important because suicide and suicidal behavior are leading causes of mortality and morbidity among adolescents, there are currently no empirically validated interventions to prevent or treat adolescent suicidal behavior, and the results of this study could frame targets for prevention and treatment.